Vaccines represent the major success of immunology and have spared countless numbers of people from infections. Despite their success, we understand little about how effective vaccines stimulate protective immune responses. Three classes of vaccine can be distinguished: i) highly effective vaccines such as yellow fever, measles and smallpox;ii) good vaccines which yield protective immunity in a majority of people including seasonal Influenza (Flu) vaccines, hepatitis B and pneumovax;and iii) vaccines which are largely not effective at the current time including HIV-AIDS, malaria, and Hepatitis C. We surmise that understanding the modus operandi of good vaccines in healthy people and understanding their shortcomings by studying hypo-responsive people will permit us to unravel the immunological principles of vaccination. Two recent developments promise to yield such understanding: i) the appreciation of the crucial role of dendritic cells in inducing and tuning the immune responses and ii) advances in high-throughput molecular profiling technologies underlying systems biology approaches. We hypothesize that a systems biology analysis will yield a comprehensive view of the immune alterations associated with a potent response to flu vaccination. We further hypothesize that efficient vaccination is associated to the early activation of antigenpresenting cells. Our goal is to identify early biomarkers of effective antibody responses to flu vaccination. Four aims are proposed to meet this goal: Aim 1: To establish the baseline immune profiles in healthy subjects. Aim 2: To establish the immune profiles of Flu vaccination in healthy subjects. Aim 3: To identify the molecular signatures of DC subset(s) in response to Flu vaccination. Aim 4: To identify the molecular signatures of activated monocytes in response to Flu vaccination.